Conditionally replicative adenoviruses (CRAds) propagate selectively in tumors and have been used to achieve extensive lysis and transduction of tumors. It is important for these replicative viruses to achieve tumor-selective replication to reduce their toxicity. Our group has developed methods of specific trans-complementation of replication-defective adenoviral vectors based on co-delivery of plasmids that enable replication. Using these methods, we have achieved replication of viruses defective in essential early regions E1 and E4. In addition, we have defined novel tumor-specific promoter (tsp) elements for achieving the desired tumor-selective replication of CRAd agents. It is our hypothesis that improving the infectivity and specificity of conditionally replicative vectors will improve their therapeutic efficacy. We intend to modify the fiber of a replicative adenovirus with an RGD motif that binds to integrins. This will provide an additional infectivity pathway different from the natural adenovirus receptor. In the second part of this project, we intend to combine this fiber modification with new methods to achieve tumor-selective replication based on the transcriptional control of E4 and/or E2 with the novel tsp elements.